Serosurveillance of SARS-CoV-2 in Welsh Blood Donors: Establishment of the surveillance system and results up to November 2022.

BackgroundIn 2020, Wales experienced some of the highest rates of confirmed COVID-19 cases in Europe. We set up a serosurveillance scheme using residual samples from blood donations to inform the pandemic response in Wales.AimTo identify changes in SARS-CoV-2 antibody seroprevalence in Wales by time, demography and location.MethodsResidual samples from blood donations made in Wales between 29 June 2020 and 20 November 2022 were tested for antibodies to the nucleocapsid antigen (anti-N) of SARS-CoV-2, resulting from natural infection. Donations made between 12 April 2021 and 20 November 2022 were also tested for antibodies to the spike antigen (anti-S) occurring as a result of natural infection and vaccination.ResultsAge-standardised seroprevalence of anti-N antibodies in donors remained stable (4.4-5.5%) until November 2020 before increasing to 16.7% by February 2021. Trends remained steady until November 2021 before increasing, peaking in November 2022 (80.2%). For anti-S, seroprevalence increased from 67.1% to 98.6% between May and September 2021, then remained above 99%. Anti-N seroprevalence was highest in younger donors and in donors living in urban South Wales. In contrast, seroprevalence of anti-S was highest in older donors and was similar across regions. No significant difference was observed by sex. Seroprevalence of anti-N antibodies was higher in Black, Asian and other minority ethnicities (self-reported) compared with White donors, with the converse observed for anti-S antibodies.ConclusionWe successfully set up long-term serological surveillance of SARS-CoV-2 using residual samples from blood donations, demonstrating variation based on age, ethnicity and location.

PITUITARY IMAGING BY MRI AND ITS CORRELATION WITH BIOCHEMICAL PARAMETERS IN THE EVALUATION OF MEN WITH HYPOGONADOTROPIC HYPOGONADISM.

Objective: A significant ambiguity still remains about which patient deserves a magnetic resonance imaging (MRI) scan of the pituitary during evaluation of hypogonadotropic hypogonadism (HH) in men. Methods: Retrospective case series of 175 men with HH referred over 6 years. Results: A total of 49.7% of men had total testosterone (TT) levels lower than the Endocrine Society threshold of 5.2 nmol/L. One-hundred forty-two patients (81.2%) had normal appearance of pituitary MRI, whereas others had different spectrum of abnormalities (empty sella [n = 16], macroadenoma [n = 8], microadenoma [n = 8], and pituitary cyst [n = 1]). In men with TT in the lowest quartile, MRI pituitary findings were not significantly different from men in the remaining quartiles (P = .50). Patients with raised prolactin had higher number of abnormal MRI findings (38.9% vs. 13.7%; P = .0014) and adenomatous lesions (macro and micro) (27.8% vs. 4.3%; P = .01) in comparison to men with normal prolactin. The prolactin levels (median [interquartile range]) were highest in men with macroadenomas in both groups (9,950 [915]; P = .007 and 300 [68.0] mU/L; P = .02, respectively), with concomitant lower levels of other pituitary hormones. Multivariate logistic regression showed an association of abnormal pituitary MRI with insulin-like growth factor 1 (IGF-1) standard deviation score (SDS) (odds ratio [OR], 1.78 [95% confidence interval (CI), 1.15 to 2.77]; P = .009) and prolactin (OR, 1.00 [95% CI, 1.00 to 1.03]; P = .01). Conclusion: MRI of the pituitary is not warranted in all patients with HH, as the yield of identifiable abnormalities is quite low. Anatomic lesions are likely to be present only when low levels of TT (<5.2 nmol/L) are found concomitantly with high levels of prolactin and/or low IGF-1 SDS. Abbreviations: CI = confidence interval; FT4 = free thyroxine; GH = growth hormone; HH = hypogonadotropic hypogonadism; IGF-1 = insulin-like growth factor; LH = luteinizing hormone; MRI = magnetic resonance imaging; OR = odds ratio; SDS = standard deviation score; TSH = thyroid-stimulating hormone; TT = total testosterone.

Primary therapy of Graves' disease and cardiovascular morbidity and mortality: a linked-record cohort study.

BACKGROUND: Graves' disease is routinely treated with antithyroid drugs, radioiodine, or surgery, but whether the choice of initial therapy influences long-term outcomes is uncertain. We evaluated cardiovascular morbidity and mortality according to the method and effectiveness of primary therapy in Graves' disease. METHODS: In this retrospective cohort study, we identified patients with hyperthyroidism, diagnosed between Jan 1, 1998, and Dec 31, 2013, from a thyroid-stimulating hormone (TSH)-receptor antibody (TRAb) test register in south Wales, UK, and imported their clinical data into the All-Wales Secure Anonymised Information Linkage (SAIL) Databank (Swansea University, Swansea, UK). Patients with Graves' disease, defined by positive TRAb tests, were selected for the study, and their clinical data were linked with outcomes in SAIL. We had no exclusion criteria. Patients were matched by age and sex to a control population (1:4) in the SAIL database. Patients were grouped by treatment within 1 year of diagnosis into the antithyroid drug group, radioiodine with resolved hyperthyroidism group (radioiodine group A), or radioiodine with unresolved hyperthyroidism group (radioiodine group B). We used landmark Kaplan-Meier and Cox regression models to analyse the association of treatment with the primary outcome of all-cause mortality and the secondary outcome of major adverse cardiovascular events (myocardial infarction, heart failure, ischaemic stroke, or death) with the landmark set at 1 year after diagnosis. We analysed the association between outcomes and concentration of TSH using Cox regression and outcomes and free thyroxine (FT4) concentration using restricted cubic-spline regression models. FINDINGS: We extracted patient-level data on 4189 patients (3414 [81·5%] females and 775 [18·5%] males) with Graves' disease and 16 756 controls (13 656 [81·5%] females and 3100 [18·5%] males). In landmark analyses, 3587 patients were in the antithyroid drug group, 250 were in radioiodine group A, 182 were in radioiodine group B. Patients had increased all-cause mortality compared with controls (hazard ratio [HR] 1·22, 95% CI 1·05-1·42). Compared with patients in the antithyroid drug group, mortality was lower among those in radioiodine group A (HR 0·50, 95% CI 0·29-0·85), but not for those in radioiodine group B (HR 1·51, 95% CI 0·96-2·37). Persistently low TSH concentrations at 1 year after diagnosis were associated with increased mortality independent of treatment method (HR 1·55, 95% CI 1·08-2·24). Spline regressions showed a positive non-linear relationship between FT4 concentrations at 1 year and all-cause mortality. INTERPRETATION: Regardless of the method of treatment, early and effective control of hyperthyroidism among patients with Graves' disease is associated with improved survival compared with less effective control. Rapid and sustained control of hyperthyroidism should be prioritised in the management of Graves' disease and early definitive treatment with radioiodine should be offered to patients who are unlikely to achieve remission with antithyroid drugs alone. FUNDING: National Institute for Social Care and Health Research, Wales.

Relationship between serum thyrotropin and urine albumin excretion in euthyroid subjects with diabetes.

BACKGROUND: Microalbuminuria represents vascular and endothelial dysfunction. Thyroid hormones can influence urine albumin excretion as it exerts crucial effects on the kidney and on the vascular system. This study explores the relationship between serum thyrotropin and urine albumin excretion in euthyroid patients with diabetes. METHODS: A total of 433 patients with type 1 or 2 diabetes were included in this retrospective cross-sectional study. Data included anthropometric measurements and biochemical parameters from diabetes clinic. Males with urine albumin creatinine ratio >2.5 and female's >3.5 mg/mmoL were considered to have microalbuminuria. RESULTS: 34.9% of the patients had microalbuminuria. Prevalence of microalbuminuria increased according to TSH quartiles (26.9, 34.6, 38.5 and 44.9%, P for trend = 0.02). In a fully adjusted logistic regression model, higher TSH concentrations were associated with high prevalence of microalbuminuria (adjusted odds ratio 2.06 [95% CI: 1.14-3.72]; P = 0.02), while comparing the highest with the lowest quartile of TSH. Multiple linear regression analysis showed an independent association between serum TSH and urine albumin creatinine ratio (ß = 0.007, t = 2.03 and P = 0.04). The risk of having microalbuminuria was higher with rise in TSH concentration in patients with younger age (<65 years), raised body mass index (≥25 kg/m2), hypertension, type 2 diabetes and hyperlipidaemia and age was the most important determinant ( P for interaction = 0.02). CONCLUSION: Serum TSH even in the euthyroid range was positively associated with microalbuminuria in euthyroid patients with diabetes independent of traditional risk factors. This relationship was strongest in patients with components of the metabolic syndrome.

SEASONAL VARIATION OF VITAMIN D AND SERUM THYROTROPIN LEVELS AND ITS RELATIONSHIP IN A EUTHYROID CAUCASIAN POPULATION.

OBJECTIVE: It is unclear whether seasonal variations in vitamin D concentrations affect the hypothalamo-pituitary-thyroid axis. We investigated the seasonal variability of vitamin D and serum thyrotropin (TSH) levels and their interrelationship. METHODS: Analysis of 401 patients referred with nonspecific symptoms of tiredness who had simultaneous measurements of 25-hydroxyvitamin D3 (25[OH]D3) and thyroid function. Patients were categorized according to the season of blood sampling and their vitamin D status. RESULTS: 25(OH)D3 levels were higher in spring-summer season compared to autumn-winter (47.9 ± 22.2 nmol/L vs. 42.8 ± 21.8 nmol/L; P = .02). Higher median (interquartile range) TSH levels were found in autumn-winter (1.9 [1.2] mU/L vs. 1.8 [1.1] mU/L; P = .10). Across different seasons, 25(OH)D3 levels were observed to be higher in lower quartiles of TSH, and the inverse relationship was maintained uniformly in the higher quartiles of TSH. An independent inverse relationship could be established between 25(OH)D3 levels and TSH by regression analysis across both season groups (autumn-winter: r = -0.0248; P<.00001 and spring-summer: r = -0.0209; P<.00001). We also observed that TSH varied according to 25(OH)D3 status, with higher TSH found in patients with vitamin D insufficiency or deficiency in comparison to patients who had sufficient or optimal levels across different seasons. CONCLUSION: Our study shows seasonal variability in 25(OH)D3 production and TSH secretion in euthyroid subjects and that an inverse relationship exists between them. Further studies are needed to see if vitamin D replacement would be beneficial in patients with borderline thyroid function abnormalities. ABBREVIATIONS: 25(OH)D2 = 25-hydroxyvitamin D2; 25(OH)D3 = 25-hydroxyvitamin D3; AITD = autoimmune thyroid disease; FT4 = free thyroxine; TFT = thyroid function test; TSH = thyrotropin; UVB = ultraviolet B.

Predicting malignancy in thyroid nodules: feasibility of a predictive model integrating clinical, biochemical, and ultrasound characteristics.

BACKGROUND: Although the majority of thyroid nodules are benign the process of excluding malignancy is challenging and sometimes involves unnecessary surgical procedures. We explored the development of a predictive model for malignancy in thyroid nodules by integrating a combination of simple demographic, biochemical, and ultrasound characteristics. METHODS: Retrospective case-record review. We reviewed records of patients with thyroid nodules referred to our institution from 2004 to 2011 (n = 536; female 84 %, mean age 51 years). All malignancy was proven histologically while benign disease was either confirmed histologically, or on cytology with minimum 36-month observation period. We focused on the following predictors: age, sex, smoking status, thyroid hormones (FT4 and TSH) and nodule characteristics on ultrasound. Variables were included in a multivariate logistic regression and bootstrap analyses were used to confirm results. RESULTS: Independent predictors of malignancy in the fully adjusted model were TSH (OR 1.53, 95 % CI 1.10, 2.12, p = 0.01), male gender (OR 3.45, 95 % CI 1.33, 8.92, p = 0.01), microcalcifications (OR 6.32, 95 % CI 2.82, 14.1, p < 0.001), and irregular nodule margins (OR 5.45, 95 % CI 1.61, 18.6, p = 0.006) Bootstrap analyses strengthened these associations and a parsimonious analysis consisting of these variables and age-group demonstrated an area under the curve of 0.77. A predictive score was sensitive (86.9 %) at low scores and highly specific (94.87 %) at higher scores for distinguishing benign from malignant disease. CONCLUSIONS: A predictive model for malignancy using a combination of clinical, biochemical, and radiological characteristics may support clinicians in reducing unnecessary invasive procedures in patients with thyroid nodules.

Weekly Intramuscular Injection of Levothyroxine following Myxoedema: A Practical Solution to an Old Crisis.

An 82-year-old female with known hypothyroidism was admitted to hospital after being found on the floor. On examination, she was unkempt, confused, bradycardic, hypothermic, and barely arousable. Initial biochemistry revealed a thyroid stimulating hormone (TSH) of >100 mU/L and free thyroxine (FT4) level of 1.5 pmol/L which supported a diagnosis of myxoedema coma. She was resuscitated and commenced on liothyronine, levothyroxine, and hydrocortisone and some improvement was made. It became apparent that she was hiding and spitting out her oral levothyroxine including levothyroxine elixir. Given the need for prompt alternative control, we sought advice from international experts where intramuscular levothyroxine was recommended. She was managed from day 50 onwards with intramuscular levothyroxine 200 mcg once a week, which was subsequently increased to 500 mcg. Thyroid function normalized and she made continual cognitive and physical progress and was discharged to a rehabilitation hospital. Her intramuscular levothyroxine was stopped and she was subsequently restarted on oral levothyroxine, with a plan for on-going close monitoring of her thyroid function. This report highlights the potential to use intramuscular levothyroxine in individuals with severe hypothyroidism arising from poor compliance with levothyroxine treatment or other potential causes such as impaired absorption.

Functional expression of inward rectifier potassium channels in cultured human pulmonary smooth muscle cells: evidence for a major role of Kir2.4 subunits.

Strong inwardly rectifying K(+) (K(IR)) channels that contribute to maintaining the resting membrane potential are encoded by the Kir2.0 family (Kir2.1-2.4). In smooth muscle, K(IR) currents reported so far have the characteristics of Kir2.1. However, Kir2.4, which exhibits unique characteristics of barium block, has been largely overlooked. Using patch-clamp techniques, we characterized K(IR) channels in cultured human pulmonary artery smooth muscle (HPASM) cells and compared them to cloned Kir2.1 and Kir2.4 channels. In a physiological K(+) gradient, inwardly rectifying currents were observed in HPASM cells, the magnitude and reversal potential of which were sensitive to extracellular K(+) concentration. Ba(2+) (100 microM ) significantly inhibited inward currents and depolarized HPASM cells by approximately 10 mV. In 60 mM extracellular K(+), Ba(2+) blocked K(IR) currents in HPASM cells with a 50% inhibitory concentration of 39.1 microM at -100 mV compared to 3.9 microM and 65.6 microM for Kir2.1 and Kir2.4, respectively. Cloned Kir2.4 and K(IR) currents in HPASM cells showed little voltage dependence to Ba(2+) inhibition, which blocked at a more superficial site than for Kir2.1. Single-channel recordings revealed strong inwardly rectifying channels with an average conductance of 21 pS in HPASM cells, not significantly different from either Kir2.1 (19.6 pS) or Kir2.4 (19.4 pS). Reverse-transcription polymerase chain reaction detected products corresponding to Kir2.1, Kir2.2 and Kir2.4 but not Kir2.3. We demonstrate that cultured HPASM cells express K(IR) channels and suggest both Kir2.1 and Kir2.4 subunits contribute to these channels, although the whole-cell current characteristics described share more similarity with Kir2.4.